This application is submitted under the Program Announcement "Collaborative Studies of Mental Disorders." The broad aims are to expand a unique, existing set of pedigrees and test candidate regions for linkage and association with bipolar disorder. For the Johns Hopkins site this represents a revised competing renewal application while for the University of Chicago site this is a new proposal. Together we propose to double the existing family resource by ascertaining an additional 80 moderate-sized families through bipolar I probands with 2 or more siblings affected with recurrent major affective disorders. All participants will be interviewed by trained psychiatrists who have established excellent inter-rater reliability. Diagnoses will be assigned by 2 non-interviewing psychiatrists who review all clinical data. This sample has already proven to be of considerable value to the field. Among clinical findings that have spawned new research directions are our reports of anticipation, parent-of-origin effects, a high prevalence of BPII among the close relatives of the bipolar I probands, and high rates of comorbid panic disorder in a subset of families. This sample provided the first support for previous evidence of linkage to the peri-centromeric region of chromosome 18, the first evidence of linkage to 18q, and the first molecular evidence for a parent-of-origin effect in bipolar disorder. Findings from prospective studies of the 2nd half of this sample demonstrate strikingly high allele-sharing between bipolar II sib pairs at several loci in 18q2l. Exploratory analyses of co- morbid panic disorder and alcoholism have also suggested methods for predicting heterogeneity between bipolar families. In addition to collecting more families, we propose to genotype the existing and additional family sets at candidate regions implicated by a recent genome-wide scan for linkage that has been completed on 68 pedigrees from this sample. We further propose to use standard and innovative linkage and association methods to extract the maximal genetic information needed to locate genes influencing susceptibility to bipolar disorder. This is the most carefully clinically assessed family set in the field. The studies generated from this family resource have already demonstrated its value and have provided testable hypotheses for further work. The enlargement, continued maintenance, and analysis of this unique family resource is important to the field and will form the basis for many future studies.